TY - JOUR
T1 - Parkin mutation affects clock gene-dependent energy metabolism
AU - Pacelli, Consiglia
AU - Rotundo, Giovannina
AU - Lecce, Lucia
AU - Menga, Marta
AU - Bidollari, Eris
AU - Scrima, Rosella
AU - Cela, Olga
AU - Piccoli, Claudia
AU - Cocco, Tiziana
AU - Vescovi, Angelo Luigi
AU - Mazzoccoli, Gianluigi
AU - Rosati, Jessica
AU - Capitanio, Nazzareno
N1 - Funding Information:
Funding: This research was funded by: “Interveento cofinanziato dal Fondo di Sviluppo e Coesione 2007–2013—APQ Ricerca Regione Puglia Programma regionale a sostegno della specializzazione intelligente e della sostenibilità sociale ed ambientale—FutureInResearch” H6SH8W9, Italy to C.P. (Consiglia Pacelli); and Ricerca Corrente 2019 to G.M. and to J.R. from the Italian Ministery of Health.
Publisher Copyright:
© 2019 by the author. Licensee MDPI, Basel, Switzerland.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Growing evidence highlights a tight connection between circadian rhythms, molecular clockworks, and mitochondrial function. In particular, mitochondrial quality control and bioenergetics have been proven to undergo circadian oscillations driven by core clock genes. Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by a selective loss of dopaminergic neurons. Almost half of the autosomal recessive forms of juvenile parkinsonism have been associated with mutations in the PARK2 gene coding for parkin, shown to be involved in mitophagy-mediated mitochondrial quality control. The aim of this study was to investigate, in fibroblasts from genetic PD patients carrying parkin mutations, the interplay between mitochondrial bioenergetics and the cell autonomous circadian clock. Using two different in vitro synchronization protocols, we demonstrated that normal fibroblasts displayed rhythmic oscillations of both mitochondrial respiration and glycolytic activity. Conversely, in fibroblasts obtained from PD patients, a severe damping of the bioenergetic oscillatory patterns was observed. Analysis of the core clock genes showed deregulation of their expression patterns in PD fibroblasts, which was confirmed in induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) derived thereof. The results from this study support a reciprocal interplay between the clockwork machinery and mitochondrial energy metabolism, point to a parkin-dependent mechanism of regulation, and unveil a hitherto unappreciated level of complexity in the pathophysiology of PD and eventually other neurodegenerative diseases.
AB - Growing evidence highlights a tight connection between circadian rhythms, molecular clockworks, and mitochondrial function. In particular, mitochondrial quality control and bioenergetics have been proven to undergo circadian oscillations driven by core clock genes. Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by a selective loss of dopaminergic neurons. Almost half of the autosomal recessive forms of juvenile parkinsonism have been associated with mutations in the PARK2 gene coding for parkin, shown to be involved in mitophagy-mediated mitochondrial quality control. The aim of this study was to investigate, in fibroblasts from genetic PD patients carrying parkin mutations, the interplay between mitochondrial bioenergetics and the cell autonomous circadian clock. Using two different in vitro synchronization protocols, we demonstrated that normal fibroblasts displayed rhythmic oscillations of both mitochondrial respiration and glycolytic activity. Conversely, in fibroblasts obtained from PD patients, a severe damping of the bioenergetic oscillatory patterns was observed. Analysis of the core clock genes showed deregulation of their expression patterns in PD fibroblasts, which was confirmed in induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) derived thereof. The results from this study support a reciprocal interplay between the clockwork machinery and mitochondrial energy metabolism, point to a parkin-dependent mechanism of regulation, and unveil a hitherto unappreciated level of complexity in the pathophysiology of PD and eventually other neurodegenerative diseases.
KW - Circadian clock
KW - Mitochondria
KW - Neurodegeneration
KW - Parkin
KW - Parkinsons disease
KW - Phenotypic reprogramming
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U2 - 10.3390/ijms20112772
DO - 10.3390/ijms20112772
M3 - Article
C2 - 31195749
AN - SCOPUS:85068174341
VL - 20
JO - International journal of molecular sciences
JF - International journal of molecular sciences
SN - 1661-6596
IS - 11
M1 - 2772
ER -